Oxatolidine of endo-bicyclo-{8 3.10{9 hex-2-ene-6-carboxldehyde

ABSTRACT

Oxazolidines obtained by the reaction of optically active ephedrines with the isomers of endo- or exo-bicyclo(3.1.0)hex-2ene-6-carboxaldehyde,   ARE DISCLOSED. These oxazolidines yield the starting materials on hydrolysis and are useful for separating and purifying said aldehydes.

United States Patent Kelly [45] Nov. 18, 1975 OXAZOLIDINE OF [56]References Cited ENDO-BICYCLO-[3.l0]HEX-2-ENE-6- UNITED STATES PATENTSCARBOXLDEHYDE 3,711,515 1/1973 Kelly 260/3433 Inventor: Robert C. Kelly,Kalamazoo, Mich.

The Upjohn Company, Kalamazoo, Mich.

Filed: Dec. 15, 1972 Appl. No.: 315,363

Published under the Trial Voluntary Protest Program on January 28, 1975as document no. B 315,363.

Related US. Application Data Division of Ser. No. 181,246, Sept. 16,1971, Pat. No. 3,71 1,515, which is a continuation-in-part of Ser. No.93,483, Nov. 27, 1970, abandoned.

Assignee:

US. Cl. 260/307 F Int. Cl C07D 263/52 Field of Search 260/307 F PrimaryE.raminerRaymond V. Rush Attorney, Agent, or Firm-Morris L. Nielsen [57]ABSTRACT Oxazolidines obtained by the reaction of optically activeephedrines with the isomers of endoor exobicyclo 3. l .0 hex-2-en e-6-carboxalde hyde,

Q CHO,

1 Claim, No Drawings OXATOLIDINE OF ENDO-BICYCLO-[3. ]IIEX-2-ENE-6-CAR-BOXLDEHYDE CROSS REFERENCE TO RELATED APPLICATIONS This application is adivision of application Ser. No. 181,246, filed Sept. 16, 1971, nowissued as US. Pat. No. 3,71 1,515, which, in turn, is acontinuation-in-part application of application Ser. No. 93,483, filedNov. 27, 1970 and now abandoned.

BACKGROUND OF THE INVENTION tive PGE and PGF a their enantiomorphs, andtheir -epimers.

Previously, the preparation of a racemic bicyclic lactone diol of theformula on on was reported by E. .1. Corey et al., J. Am. Chem. Soc. 91,5675 (1969), and later disclosed in an optically active form by E. J.Corey et al., J. Am. Chem. Soc. 92, 397 (1970). Conversion of thisintermediate to PGE and PGF a either in dl-form or optically activeform, was disclosed in those publications.

It is well known that the 'prostaglandin structures have several centersof asymmetry and therefore exist as stereoisomers (see Nugteren et al.,Nature 212, 38-39 (1966); Bergstrom et al., Pharmacol. Rev. 20, 1(1968)). Each fonnula for PGE PGF PGE and POI- herein represents amolecule of the optically active naturally-occurring form of theprostaglandin.

POE- has the following structure:

0 ll \QA coon on on PGF has the following structure:

, on on PGE has the following structure:

PGF a has the following structure:

on I

on on See also FIGS. XVI, XXII, XXIV, and XXVI herein, which areidentical to the above formulas when represents attachment of hydroxylin the a (S) configuration. The mirror image of each formula representsa molecule of the enantiomorphic form of that prostaglandin. Thus, forexample, ent-PGE refers to the enantiomorph of PGE The racemic or dlform of the prostaglandin consists of equal numbers of two types ofmolecules, e.g. a natural-configuration prostaglandin and itsenantiomorph. If one of the optically active isomers has dextro opticalrotatory power, the other has an equal degree of laevo optical rotatorypower. A racemic mixture of equal quantities of dand l-isomers exhibitsno optical rotation. The reaction of the components of a racemic mixturewith an opticallyactive substance results in the formation ofdiastereomers having different physical properties, e.g., degree ofsolubility in a solvent. Another term used herein is IS-epimer." Whenreferred to one of the above prostaglandins, it identifies a moleculehaving the opposite configuration at the C-1 5 atom. Thus, l5B-PGErefers to the product having the B (R) configuration at carbon 15 ascompared with the 01(8) configuration for PGE PGE PGF a PGF and PGA andtheir esters, acylates, and pharmacologically acceptable salts, areextremely potent in causing various biological responses. For thatreason, these compounds are useful for pharmacological purposes. See,for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), andreferences cited therein. A few of those biological responses aresystemic arterial blood pressure lowering in the case of the PGE PGF pand PGA compounds as measured, for example, in anesthetized(pentobarbital sodium) pentolinium-treated rats with indwelling aorticand right heart cannulas; pressor activity, similarly measured, for thePGF a compounds; stimulation of smooth muscle as shown, for example, bytests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon;potentiation of other smooth muscle stimulatns; antilipolytic activityas shown by antagonism of epinephrine-induced mobilization of free fattyacids or inhibition of the spontaneous release of glycerol from isolatedrat fat pads; inhibition of gastric secretion in the case of the PGE andPGA compounds as shown in dogs with secretion stimulated by food orhistamine infusion; activity on the central nervous system; decrease ofblood platelet adhesiveness as shown by platelet-toglass adhesiveness,and inhibition of blood platelet aggregation and thrombus formationinduced by various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., AOP, ATP, serotonin, thrombin, and collagen;and in the case of the PGE compounds, stimulation of epidermalproliferation and keratinization as shown when applied in culture toembryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds, and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about ug. to about 10mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce the controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 ug. to about 500 pg.per kg. of body weight per minute, or in a total daily dose by injectionor infusion in the-range about 0.1 to about mg. per kg. of body weightper day, the exact dose depending on the age, weight, and condition ofthe patient or animal, and on the frequency and route of administration.

The PGE PGF a and PGF 3 compounds are useful whenever it is desired toinhibit platelet aggregation, to reduce the adhesive character ofplatelets, and to remove or prevent the formation of thrombi in mammals,including man, rabbits, and rats. For example, these compounds areuseful in the treatment and prevention of myocarbial infarcts, to treatand prevent post-operative thrombosis, to promote patency of vasculargrafts following surgery, and to treat conditions such asatherosclerosis, arteriosclerosis, blood clotting defects clue tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g.,intravenously, subcutaneously, intramuscularly, and in the form ofsterile implants for prolonged action. For rapid response, especially inenergency situations, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE PGF a and PGF compounds are especially useful as additives tobfivod, blood products, blood substitutes, and other fluids which areused in artificial extracorporeal circulation and perfusion of isolatedbody portions, e.g., limbs and organs, whether attached to the originalbody, detached and being preserved or prepared for transplant, orattached to a new body. During these circulations and perfusions,aggregated platelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to l0 mg. per liter of circulating fluid. It is especially 4useful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits,,monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore PGE for example, is useful in place of or in combination withless than usual amounts of these known smooth muscle stimulators, forexample, to relieve the symptoms of paralytic ileus, or to control orprevent atonic uterine bleeding after abortion or delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about 50 pg. per kg. of.body weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.01 to 2 mg. per kg. of body weight per day, the exactdose depending on the age, weight, and condition of the patient oranimal.

The PGE PGF 3 and PGA compounds are useful as hypotensive agents toreduce blood pressure in mammals including man. For this purpose, thecompounds are administered by intravenous infusion at the rate of about0.01 to about 50 ',u.g. per kg. of body weight per minute, or in singleor multiple doses of about 25 to 500 pg. per kg. of body weight totalper day.

The PGE PGF and PGF 3 compounds are useful in place of oxytocin toinduce labor in pregnant female animals, including man, cows, sheep, andpigs, at or near term, or in pregnant animals with intrauterine death ofthe fetus from about 20 weeks to term. For this purpose, the compound isinfused intravenously at a dose 0.01 to 50 pg. per kg. of body weightper minute until or near the termination of the second stage of labor,i.e., expulsion of the fetus. These compounds are especially useful whenthe female is one or more weeks post-mature and natural labor has notstarted, or 12 to g 60 hours after the membranes have ruptured andnatural labor has not yet started.

The PGE PGF a and PGF 5 compounds are useful for controlling thereproductive cycle in ovulating female mammals, including humans andother animals. For that purpose, PGF for example, is administeredsystemically at a dose level in the range 0.01 mg. to about 20 mg. perkg. of body weight, advantageously during a span of time startingapproximately at the time ovulation and ending approximately at the timeof menses or just prior to menses. Additionally, expulsion of an embryoor a fetus is accomplished by similar administration of the compoundduring the first third of the normal mammalian gestation period. Becausethe PGE compounds are potent antagonists of epinephrine-inducedmobilization of free fatty acids, they are useful in experimentalmedicine for both in vitro and in vivo studies in mammals, includingman, rabbits, and rats, intended to lead to the understanding,prevention, symptom alleviation, and cure of diseases involving abnormallipid mobilization and high free fatty acid levels, e.g., diabetesmellitus, vascular diseases, and hyperthyroidism.

The PGE compounds promote and accelerate the growth of epidermal cellsand keratin in animals, in-

cluding humans, and other animals. For that reasons,

these compounds are useful to promote and accelerate healing of skinwhich has been damaged, for example, by burns, wounds, and abrasions,and after surgery. These compounds are also useful to promote andaccelerate adherence and growth of skin autografts, especially small,deep (Davis) grafts which are intended to cover skinless areas bysubsequent outward growth rather than initially, and to retard rejectionof homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as in mammals, including humans and otheranimals. For that purpose, PGF a for example, is administeredsystemically at a dose level in the range 0.01 mg. to about 20 mg. perkg. of body weight, advantageously during a span of time startingapproximately at the time of menses or just prior to menses.Additionally, expulsion of an embryo or a fetus is accomplished bysimilar administration of the compound during the first third of thenormal mammalian gestation period. Because the PGE compounds are potentantagonists of epinephrine-induced mobilization of free fatty acids,they are useful in experimental medicine for both in vitro and in vivostudies in mammals, including man, rabbits, and rats, intended to leadto the understanding, prevention, symptom alleviation, and cure ofdiseases involving abnormal lipid mobilization and high free fatty acidlevels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.

The PGE compounds promote and accelerate the growth of epidermal cellsand keratin in animals, including humans, and other animals. For thatreason, these compounds are useful to promote and accelerate healing ofskin which has been damaged, for example, by burns, wounds, andabrasions, and after surgery. These compounds are also useful to promoteand accelerate adherence and growth of skin autografts, especiallysmall, deep (Davis) grafts which are intended to cover skinless areas bysubsequent outward growth rather than initially, and to retard rejectionof homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueoussolution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. In some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containing 5to 1000 pg/ml. of the PGE compound. Especially for topical use, theseprostaglandins are useful in combination with antibiotics, for example,gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, andoxytetracycline, with other antibacterials, for example, mafenidehydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, andwith corticoid steroids, for example, hydrocortisone, prednisolone,methylprednisolone, and fluprednisolone, each of those being used in thecombination at the usual concentration suitable for its use alone.

SUMMARY OF THE INVENTION It is the purpose of this invention to provideprocesses for the production of compounds useful in the preparation ofprostaglandins commercially in substantial amount and at reasonablecost. It is a further pur pose to provide processes for preparingcertain intermediates in optically active forms. It is still a furtherpurpose to provide a process for preparing racemic and optically activePGE PGF a and PGF B and PGA their enantiomorphs, and their l5-epimers.

The presently described processes and intermediates are useful forpreparing PGE PGF a PGF and lPGA and their racemic forms, which areknown to be useful for the above-described pharmacological purposes. Theprocesses and intermediates disclosed herein are also useful for thepreparing enantiomorphic PGE PGF a PGF and PGA and PGE FOR, PGF p andPGA their enantiomorphs, and their ISB-epimers, each one of which isuseful for the above-described pharmacological purposes, and is used forthose purposes in the same manner as described above. These novelcompounds are substantially more specific with regard to potency incausing prostaglandin-like biological responses. Therefore, each ofthese novel prostaglandin-type compounds is surprisingly andunexpectedly more useful than one of the corresponding above-mentionedknown prostaglandins for at least one of the pharmacological purposesindicated above for the latter, because it has a different and narrowerspectrum of biological potency than the known prostaglandins, andtherefore is more specific in its activity and causes smaller and fewerundesired side effects than when the known prostaglandin is used for thesame purpose.

Thus, there is provided a process for preparing an optically activetricyclic lactone glycol of the formula or the mirror image thereof, ora racemic compound of that formula and the mirror image thereof, whereinY is l-pentyl or l-pent-Z-ynyl, and indicates attachment of the moietyto the cyclopropane ring in exo or endo configuration and to the sidechain in alpha or beta configuration, which comprises the steps of:

a. converting optically active or racemic bicyclo- [3. l.0]hex-2-ene--carboxaldehyde to an optically active acetal of theformula or the mirror image thereof, or a racemic compound of thatformula and the mirror image thereof, wherein R and R are alkyl of oneto 4 carbon atoms, inclusive or, when taken together,

wherein R R R R R and R are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or phenyl, with the proviso that not more than one of the R'sis phenyl and the total number of carbon atoms is from 2 to 10,inclusive; x is zero or one, and is as defined above;

b. transforming said optically active or racemic acetal to an opticallyactive tricyclic mono or dihaloketone of the formula or the mirror imagethereof, or a racemic compound of that formula and the mirror imagethereof, wherein R R and are as defined above, and wherein R is bromo orchloro, and R is hydrogen, bromo, or chloro;

c. transforming said optically active or racemic tricyclic mono ordihaloketone to an optically active tricyclic ketone of the formula orthe mirror image thereof, or a racemic compound of that formula and themirror image thereof, wherein R and R and are as defined above;

d. oxidizing said optically active or racemic tricyclic ketone to anoptically active tricyclic lactone acetal of the formula or the mirrorimage thereof, or a racemic compound of that formula and the mirrorimage thereof, wherein R R and are as defined above;

e. hydrolyzing said optically active or racemic tricyclic lactone acetalto an optically active tricyclic lactone aldehyde of the formula tonealkene or alkenyne of the formula or the mirror image thereof, or aracemic compound of that formula and the mirror image thereof, wherein Yand are as defined above; and

g. hydroxylating said optically active or racemic tricyclic lactonealkene or alkenyne to form said optically active or racemic tricycliclactone glycol. Reference to Chart A, herein, will make clear thetransformation from bicyclic aldehyde I to tricyclic lactone glycol VIIIby steps a-g, inclusive. Formulas l-X, inclusive, hereinafter referredto, are depicted in Chart A, wherein R and R are alkyl of one to 4carbon atoms, inclusive, or, when taken together,

wherein R R R R R and R are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or phenyl, with the proviso that not more than one of the R'sis phenyl and the total number of carbon atoms is from 2 to 10,inclusive; and x is Zero or one; wherein R is alkyl of one to 5 carbonatoms, inclusive, R is bromo or chloro, and R is hydrogen, bromo, orchloro, wherein Y is l-pentyl or l-pent-2-ynyl; wherein W is l-pentyl,cis l-pent- 2-enyl, or l-pent-2-ynyl; and wherein indicates attachmentof the moiety to the cyclopropane ring in exo or endo configuration, orattachment of the hydroxyl to the side chain in alpha or betaconfiguration.

In the formulas herein, the broken line attachments to a ring representsubstituents in alpha configuration, i.e., below the plane of the paper.The wavy line indicates attachment of a group to a cyclopentane orlactone ring in alpha or beta configuration, or it indicates attachmentto a cyclopropane ring in exo or endo configuration, or it indicatesattachment to the G15 carbon of the prostamoic acid skeleton in a (S) orB (R) configuration. The fon'nula of each intermediate as drawn hereinis intended to represent the particular optical isomer which istransformed by the processes herein to an optically active prostaglandinhaving the natural configuration of prostaglandins obtained frommammalian tissues. The mirror image of each formula then represents amolecule of the enantiomorphic form of that intermediate. The expressionracemic compound refers to a mixture of the optically active isomerwhich yields the natural configuration prostaglandin and the opticallyactive isomer which is its enantiomorph.

The bicyclic aldehyde of Formula I in Chart A exists in (HART ACI[=Cl[-Y 2 VII vm oli Oll a number of isomeric forms. With respect tothe attachment of the CI-lO group, it exists in two isomeric forms, exoand endo. Also, with respect to the position of the cyclopentene doublebond relative to the -CH0 group, each of the exo and endo forms existsin two optically active (dor I-) forms, making in all four isomers. Eachof those isomers separately or mixtures thereof undergo the reactionsherein for producing prostaglandin intermediates and products. Forracemic productsthe unresolved isomers are used. For the opticallyactive prostaglandins, the aldehyde or subsequent intermediate isomersare resolved by my new process disclosed herein, and are used forpreparing the optically active products. The preparation of the exo andendo aldehydes is discussed below under Preparations.

In carrying out step a, bicyclic aldehyde I is transformed to acetal IIby methods known in the art. Thus, aldehyde I is reacted with either analcohol of one to 4 carbon atoms, e.g., methanol, ethanol, propanol, orbutanol in their isomeric forms, or mixture of such alcohols, or,preferably, a glycol having the formula am a l t; I ia 1 l wherein R R RR R and R are hydrogen, alkyl of one to 4 carbon atoms, inclusive, orphenyl, with the proviso that not more than one of the R's is phenyl andthe total number of carbon atoms is from 2 to 10, inclusive; and x iszero or one. Examples of suitable glycols are ethylene glycol,1,2-propanediol, l,2-hexanediol, l,3-.butanediol, 2,3-pentanediol,2,4-hexanediol, 3,4- octanediol, 3 ,5-nonanediol, 2,2-dimethyll ,3-propanediol, 3,3-dimethyl-2,4-heptanediol, 4-ethyl-4-methyl-3,5-heptanediol, phenyl-1,2-ethanediol, and lphenyl-l,2-propanediol.

The step-a reaction is carried out under a variety of conditions usingprocedures generally known in the art. Thus, the reactants are dissolvedin benzene and the mixture heated to remove the water formedazeotropically. To accelerate the reaction, there may be added an acidcatalyst such as p-toluenesulfonic acid, trichloroacetic acid, zincchloride, and the like. Alternatively, the reactants, together with theacid catalyst and a water scavenger such as trimethyl orthoformate arewarmed to 40l00 C. in an inert solvent such as benzene, toluene,chloroform, or carbon tetrachloride. The ratio of the aldehyde to theglycol is preferably between lzl and 1:4.

In transforming acetal II to ketone IV, reactions known in the art foranalogous compounds are employed. In carrying out step b, acetal II isreacted with a ketene R' R C=C=O, for example HBrC=C=O, HClC=C=O, BrC=C=O, or Cl C=C=O. For convenience, keteneCl C=C=O is preferred. It ispreferably generated in situ by the reaction of a O.5-to-2.0-fold excessof dichloroacetyl chloride in the presence of a tertiary amine, e.g.,triethylamine, tributylamine, pyridine, orl,4-diazabicyclo[2.2.2]octane, in a solvent such as n-hexane,cyclohexane, or mixture of isomeric hexanes (Skellysolve B) at atemperature of from 0 to C. (See, for example, Corey et al., TetrahedronLetters No. 4, pp. 307-310, 1970). Alternatively, the

ketene Cl C=C=O is generated by adding a trichloroa- :yl halide to zincdust suspended in the reaction vessel, omitting the tertiary amine.

In carrying out step c, monoor dihaloketone III is 5 reduced with a2-to-5-fold excess of zinc dust over the stoichiometric ratio of Zn:2 CIin methanol, ethanol, ethylene, glycol, and the like, in the presence ofacetic acid, ammonium chloride, sodium bicarbonate or sodium dihydrogenphosphate. Alternatively, the reaction is carried out with aluminumamalgam in a watercontaining solvent such as methanol-diethyletherwater, tetrahydrofuran-water, or dioxane-water, at about O50 C.

In carrying out step d, tricyclic acetal ketone IV is converted to alactone by methods known in the art, for example by reaction withhydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoicacid, and the like, in the presence of a base such as alkali hydroxide,bicarbonate, or orthophosphate, using a preferred molar ratio ofoxidizer to ketone of 1:1.

In carrying out step e, lactone acetal V is converted E to aldehyde VIby acid hydrolysis, known in the art, using dilute mineral acids, aceticor formic acids, and the like. Solvents such as acetone, dioxane, andtetrahydrofuran are used.

In carrying out step f, aldehyde VI is transformed to the Formula-VIIalkene or alkenyne, for example by means of an ylid as in the Wittigreaction. A l-hexyl halide or l-hex-3-ynyl halide, preferably thebromide, is used to prepare the Wittig reagent, e.g.hexyltriphenylphosphonium bromide or (hex-3-ynyl)triphenylphosphoniumbromide.

In carrying out step g, the Formula-VII alkene or alkenyne ishydroxylated to glycol VIII by procedures known in the art. See SouthAfrican Pat. No. 69/4809 issued July 3, 1970. In the hydroxylation ofthe respective endo or exo alkenes, various isomeric glycols areobtained depending on such factors as whether the CI-I=CH moiety in VIIis cis or trans, and whether a cis or a trans hydroxylation reagent isused. Thus, endo-cis olefin gives a mixture of two isomeric erythroglycols of Formula VIII with a cis hydroxylation agent, e.g., osmiumtetroxide. Similarly, the endotrans olefin gives a similar mixture ofthe same two erythro glycols with a trans hydroxylation agent, e.g.,hydrogen peroxide. The endo-cis olefins and the endo-trans olefins give6 H U" f, T similar mixtures of two threo glycol isomers with trans XI xand cis hydroxylation reagents, respectively. These var- 0 1| .iousglycol mixtures are separated into individual isoi mers by silica gelchromatography. However, this separation is usually not necessary, sinceeach isomeric erythro glycol and each isomeric threo glycol is useful asan intermediate according to this invention and the processes outlinedin Chart A to produce intermediate i mom" products of Formula X andthen, according to Charts C through F hereinafter to produce the otherfinal prod- P "T" I,

ucts of this invention. Thus, the various isomeric glycol H mixturesencompassed by Formula VIII produced from OH the various isomericolefins encompassed by Formula VII are all useful for these samepurposes. /\/E/\/\ 0 on There is further provided by this invention aprocess CIH" for preparing an optically active bicyclic lactone diol ofthe formula or"? o'rnr XIV H i O O C m n zw w x X WV H W 0 A0 A P H T sP T O CHART F n-Cslln 2/ H 0 v Iv a H 0 fi Z I 0 m I X fiv 5 O l 2 I V HX CHART D XXVI or the mirror image thereof, or a racemic compound ofXVIII that formula and the mirror image thereof, wherein W is l-pentyl,cis l-pent-Z-enyl, or l-pent-Z-ynyl, and indicates attachment of thehydroxyl to the side chain in alpha or beta configuration, whichcomprises the steps of:

a. replacing teh glycol hydrogens of an optically active tricycliclactone glycol of the formula 5 Oil Oil (HA RT E or the mirror imagethereof, or a racemic compound of that formula and the mirror imagethereof, by an alkanesulfonyl group, R O S, wherein R is alkyl of one to5 carbon atoms, inclusive, and indicates attachment of the moiety to thecyclopropane ring in exo or endo configuration and to the side chain inalpha or beta configuration; and

b. mixing the compound formed in step a with water ll-CsHn at atemperature in the range of 0 to 60 C. to form said optically active orracemic bicyclic lactone diol.

I I O Glycol VIII is transformed by steps h and i into diol X as shownin Chart A. The procedures for forming the Formula-IX bis(alkanesulfonicacid) ester by replacing the glycol hydrogen by an alkanesulfonyl group,and subsequently hydrolyzing that ester to diol X are known in the art(see South African patent cited immediately above).

In Chart A, there are differences in the terminal groups on the sidechains of Formulas VII and VIII. In Formula VII, Y is limited tol-pentyl or l-pent-2-ynyl whereas in Formula VIII, W includes l-pentyl;cis lpent-Z-enyl, or l-pent-2-ynyl. The compounds of Formula VIII, IX,or X wherein W is cis 1-pent-2-enyl are obtained by reducing the C E C-moiety of the pent-Z-ynyl group to cis CH=CI-l before or after any ofthe steps h or i, i.e., at any stage after the hydroxylation of theCI-I=CH moiety in step g. For that purpose, there are used any of theknown reducing agents which reduce an acetylenic linkage to acis-ethylenic linkage. Especially preferred for that purpose are diimideor hydrogen and a catalyst, for example, palladium (5%) on bariumsulfate, especially in the presence of pyridine. See Fieser et al.,Reagents for Organic Synthesis, pp. 556-567, John Wiley & Sons, Inc.,New York, NY. (1967).

There is further provided a process for preparing an optically activebicyclic lactone diol of the formula or the mirror image thereof, or aracemic compound of that formula and the mirror image thereof, wherein Wis l-pentyl, cis l-pent-2-enyl, or l-pent-2-ynyl, and indicatesattachment of the hydroxyl to the side chain in alpha or betaconfiguration, which comprises starting with an optically activetricyclic lactone alkene or alkenyne of the formula or the mirror imagethereof, or a racemic compound of that formula and the mirror imagethereof, wherein Y is l-pentyl or l-pent-Z-ynyl and indicates attachmentof the moiety to the cyclopropane ring in exo or endo configuration, andsubjecting said alkene or alkenyne successively to the followingreactions:

a. oxidation of the -Cl-I=CI-I moiety to an epoxy ring,

b. hydrolysis of the resulting epoxide to a mixture of said bicycliclactone diol and a tricyclic lactone glycol,

c. formolysis of said mixture to form a diformate of said bicycliclactone diol, and

d. hydrolysis of said diformate to said bicyclic lactone diol,

with the proviso that, when W is cis l-pent-Z-enyl, the C C moiety isreduced to cis CH=CH be fore or after any of the steps b to (1.

Reference to Chart B, herein, will make clear the transformation fromthe Formula-VII lactone alkene or alkenyne to diols X a and X p FormulasVII, X X3 XXXVIII, XXXIX, and XL, hereinafter referred to, are depictedin Chart B, wherein E and M are both hydrogen or wherein one of E and Mis hydrogen and the other is formyl, wherein Y is l-pentyl or l-pent-Z-ynyl, wherein indicates attachment of the moiety to the cyclopropanering in exo or endo configuration, or attachment of OE and OM in threoor erythro configuration, or attachment to the side chain in alpha orbeta configuration, and wherein o I "1 indicates attachment of theepoxide oxygen to the side chain in alpha or beta configuration.

The Formula-VII alkene or alkenyne, prepared by steps a-f of Chart A, istransformed to epoxide XXVIII by mixing reactant VII with a peroxycompound which is hydrogen peroxide or, preferably, an organicpercarboxylic acid. Examples of useful organic percarboxylic acids forthis purpose are performic acid, peracetic acid, 'perlauric acid,percamphoric acid, perbenzoic acid, m-chloroperbenzoic acid, and thelike. Peracetic acid is especially preferred.

The peroxidation is advantageously carried out by mixing the reactantVII with about one equivalent of the per acid or hydrogen peroxide,advantageously in a diluent, for example, chloroform. The reactionusually proceeds rapidly, and the Formula-XXXVIII epoxide is isolated byconventional methods, for example, evaporation of the reaction diluentand removal of the acid corresponding to the per acid if one is used. Itis usually unnecessary to purify the oxide before using it in the nextstep.

Two procedures are available for transforming epoxide XXXVIII to dioldiformate XL. In one, the epoxide is hydrolyzed to a mixture of glycolXXXIX, wherein E and M are hydrogen, and diol X a 5 For this purpose, asolution of dilute formic acid in an inert miscible solvent such asacetone, dimethyl sulfoxide, ethyl acetate, or tetrahydrofuran is used.Reaction temperatures of 20 C. to C. may be employed, although about 25C. is preferred. At lower temperatures, the desired mixture is producedinconveniently slowly. At higher temperatures, undesired side reactionsreduce the yield of the desired mixture. Thereafter, the glycoldiolmixture is contacted with formic acid, preferably substantially 100%formic acid, at about 25 C. to form the diol formate. By substantially100% formic acid is meant a purity of at least 99.5%.

In the other procedure, epoxide XXXVIII is subjected to formolysisdirectly. Preferably, substantially 100% formic acid is used, at about25 C. An inert solvent such as dichloromethane, benzene, or diethylether may be employed.

In either procedure, glycol monoformate XXXIX, wherein one of E and M ishydrogen and the other is formyl, is often present as an intermediate.It is ordinarily not isolated, but is converted to diol diformate XL insubstantially 100% formic acid.

The diol diformate XL is obtained as a mixture of isomers in which theformyl group on the side chain are in the alpha and beta configurations.The mixture is converted directly to the diols X a and X 3 withoutseparation. For this purpose, the diol diformates are contacted with aweak base such as an alkali metal carbonate, bicarbonate, or phosphate,preferably sodium or potassium bicarbonate, in a lower alkanol, forexample methanol or ethanol. For this base hydrolysis, a temperaturerange of C. to 50 C. is operable, preferably about 25 C.'The product isa mixture containing the diols X a and X p wherein the hydroxyl on theside chain is in the alpha and beta configuration. Separation of thealpha and beta diols is done by known procedures. Especially useful hereis chromatography, for example on silica gel or alumina.

In Chart B, there are differences in the terminal groups on the sidechains of Formulas VII, XXXVIII, XXXIX, XL, X a and X p In Formula VII,Y is limited to l-pentyl or 1-pent-2-ynyl whereas in the other formulasW includes l-pentyl, cis l-pent-Z-enyl, or 1- pent-2-ynyl. Similarly toChart A above, the compounds wherein W is cis l-pent-2-enyl are obtainedby reducing the CE C moiety to cis -CI-I=CH by methods known in the artat any stage after the epoxidation of the CI-I=CH- moiety of compoundVII.

The formation of PGE or PGF from the Formula-X lactone diol intermediateis done by the steps shown in Charts C and E known in the art. See E. J.Corey et al., J. Am. Chem. Soc. 91, 5675 (1969). The Formula-XI compoundis within the scope of the Formula-X diol when W is n-C l-I Theformation of PGF 5 by carbonyl reduction of PGE is known in the art. Forthis reduction, use is made of any of the known ketonic carbonylreducing agents which do not reduce ester or acid groups orcarbon-carbon double'bonds when the latter is undesirable. Examples ofthose are the metal borohydrides, especially sodium, potassium, and zincborohydrides, lithium (tri-tert-butoxy) aluminum hydride, metaltrialkoxy borohydrides, e.g., sodium trimethoxyborohydride, lithiumborohydride, diisobutyl aluminum hydride, and when carbon-carbon doublebond, especially cis, reduction is not a problem, the boranes, e.g.,disiamylborane. As is known, this method gives a mixture of PGF a andPGF B which are readily separated by chromatography. The formation ofPGA by acidic dehydration of PGE is known in the art. See, for example,Pike et al., Proc. Nobel Symposium l 1, Stockholm (1966), lntersciencePublishers, New York, p. 162 (1967), and British Specification1,097,533. Alkanoic acids of 2 to 6 carbon atoms, inclusive, especiallyacetic acid, are preferred acids for this acidic dehydration.Diluteaqueous solutions of mineral acids, e.g., hydrochloric acid,especially in the presence of a solubilizing diluent, e.g.,.tetrahydrofuran, are also useful as reagents for this acidicdehydration.

With regard to Formulas II to XXXIV, examples of alkyl of one to 4carbon atoms, inclusive, are methyl, ethyl propyl, butyl, and isomericforms-thereof. Examples of alkyl of one to 8 carbon atoms, inclusive,are those given above, and pentyl, hexyl, heptyl, octyl, and isomericforms thereof. In Formulas XI-XVI and elsewhere, n-C l-l represents thenormal-pentyl group, and TI-1P represents the tetrahydropyranyl group.

There is further provided a process for preparing PGE dl-PGE or theirIS-epimers, which comprises starting with an optically active glycol ofthe formula 3 3 on 011 or a racemic compound of that formula and themirror image thereof, wherein indicates attachment of the moiety to thecyclopropane ring in exo or endo configuration and to the side chain inalpha or beta configuration, and subjecting said glycol successively tothe following reactions:

a. replacement of the glycol hydrogens by an alkanesulfonyl group, R OS, wherein R is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of 0 to C. to form abicyclic lactone diol of S and R configuration;

c. separation of said diols of S and R configuration;

d. transformation to a bis(tetrahydropyranyl)ether;

e. reduction of the lactone oxo group to a hydroxy group;

f. Wittig alkylation with a compound of the formula Hal(Cl-I COOI-Iwherein Hal is bromo or chloro;

g. oxidation of the 9-hydroxy to 0x0; and

h. transformation of the two tetrahydropyranyloxy groups to hydroxygroups;

with the proviso that, before or after any of the steps a to h, the C-'C moiety is reduced to cis CI-I=)\ CH.

Reference to Charts A and D, herein, will make clear the transformationfrom bicyclic aldehyde 1 to PGE ent-PGE ,.-dl-PGE or their IS-epimers.ln Chart D, Z is cis 1-pent-2-enyl or l-pent-2-ynyl, and and THP are asdefined above. A kay intermediate for this sequenceis the racemic oroptically active lactone aldehyde VI. The Formula-VI compound isprepared from racemic bicyclic aldehyde I by steps a-e of Chart A andthereafter resolved in an optically active form by the method disclosedhereinafter via the oxazolidine of Example 15. Optionally, the Formula-laldehyde is resolved as disclosed hereinafter in Example 13, andthereafter converted to the optically active Formula-VI compound.

In carrying out step f of Chart A, the Wittig reaction is employed,using a l-hex-2-ynyl chloride, bromide, or iodide, preferably bromide,to prepare the necessary Wittig reagent by processes known in the art.

In carrying out steps g through i of Chart A, the procedures forhydroxylating the FormulaVII alkenyne wherein Y is 1-pent-2-ynyl,forming the Formula-IX bis-(alkanesulfonic acid) ester, and hydrolyzingthat ester to the Formula-X lactone diol are generally known in the art.See South African Patent 69/4809 issued July 3, 1970. The Formula-Xlactone diol, which contains botha and ,B epimers as produced, yieldsthe final product as a mixture of PGE and its 15-epimer. It ispreferable that the diol a and B epimers be separated rather than thefinal product epimers. Silica gel chromatography is employed for thispurpose. The Formula-X B-epimer then leads to the dl-15B-PGE Inconverting glycol VIII, wherein W is l-pent-2-ynyl, to the Formula-XXIIproduct. the C E C moiety is reduced to cis -CH=CH at any stage. Thus,glycol VIII is optionally reduced before replacing the glycol hydrogenswith an alkanesulfonyl group; or any of the Formula-IX, -X, -XVllI,-XIX, -XX, or -XXI intermediates is optionally reduced. Reducingreagents, catalysts, and conditions are used which do not substantiallyreduce CH=CH. A suitable method is to hydrogenate over a Lindlarcatalyst, i.e. 5% palladiumon-barium sulfate catalyst, in the presenceof quinoline. Methanol or like inert solvent or diluent is used and thepressure is low, advantageously slightly above atmospheric andordinarily not above about two atmospheres. The resulting products areisolated by silica gel chromatography.

The formation of PGE from the Formula-XVII diol intermediate by thesteps of Chart D, other than the reduction step above-described,generally follows procedures known in the art and discussed above underthe formation of PGE There is further provided a process for preparingPGF a dl-PGF a or their IS-epimers, in which glycol VIII, wherein W isl-pent-2-ynyl, is transformed to diol XVII, wherein Z is cisl-pent-2-enyl or l-pent-2- ynyl, and thence to the Formula-XXVIproducts, as depicted by the steps of Chart F. Accordingly, diol XVII isreduced to lactol XXV which is then alkylated by a Wittig reaction. Asin the process for PGEg, the -C=C moiety is reduced to cis CI-I=Cl-I atany stage between the glycol and the end-product. As in the process forPGE the optical isomers of the intermediates yield the corresponding PGFor ent- PGF a the racemic intermediates yield racemic PGF a theoptically active (1- and ,B-configuration intermediates yield thecorresponding PGF a ent- PGF or their IS-epimers.

The formation of racemic and optically active PGF p from racemic andoptically active PGE generally follows procedures known in the art,e.g., by carbonyl reduction with borohydride, discussed above under theformation of PGF p The formation of racemic and optically active PGAfrom racemic and optically active POE likewise follows procedures knownin the art, e.g., by acidic dehydration, discussed above under theformation of PGA There is further provided a process for resolving aracemic mixture of an oxo compound of the formula and of the mirrorimage thereof, wherein R and R are alkyl of one to 4 carbon atoms,inclusive, or, when taken together,

sive; x is zero or one, and indicates attachment of the moiety to thecyclopropane ring in exo or endo configuration, which comprises thesteps of:

a. converting the oxo compound by reaction with an 5 optically activeephedrine to a mixture of oxazolidine diastereomers, b. separating atleast one oxazolidine diastereomer from said mixture, c. hydrolyzingsaid oxazolidine to free the optically active oxo compound, and d.recovering said optically active oxo compound. In carrying out theresolution of the Formula-I bicyclic aldehyde, there is prepared anoxazolidine by reaction of the aldehyde with an optically activeephedrine, l5 e.g. dor l-ephedrine, or dor l-pseudoephedrine. Ap-

proximately equi-molar quantities of the reactants are employed in asolvent such as benzene, isopropyl ether, or dichloromethane. Althoughthe reaction proceeds smoothly over a wide range in temperature, e.g.,l080 C it is preferred that it be done in the range 20 to C. to minimizeside reactions. with the Formula-I compound, it occurs quickly, withinminutes, whereupon the solvent is removed, preferably under vacuum. Theproduct consists of the diastereomers of 2 the aldehyde-ephedrineproduct, i.e. the oxazolidines.

At least one of the diastereomersis separated by methods known in theart, including crystallization and chromatography. In this instance,crystallization is used as the preferred method. Repeatedrecrystallization of the thus-obtained solid oxazolidine from a suitablesolvent, e.g., isopropyl ether, yields one of the diastereomers insubstantially pure form. The oxazolidine is then hydrolyzed byprocedures known in the art to release the aldehyde. However, I havefound silica gel wet with water surprisingly effective, using the silicagel in a column, with the further beneficial effect that the column actsas a means of separating the ephedrine from the aldehyde. The elutedfractions are then evaporated to yield the desired resolved Formula-Ialdehyde.

The mother liquor from the recrystallized diastereomer contains theoptical isomer having opposite configuration. A preferred method forisolating this second diastereomer, however, is to prepare theoxazolidine of the racemic aldehyde using ephedrine of the oppositeconfiguration to that first employed above, and there afterrecrystallizing as above. Finally, hydrolysis and recovery yield theresolved Formula-I aldehyde in opposite configuration to that firstobtained above.

I have further found that this method is generally applicable forresolving aldehydes and ketones, and is useful for resolving not onlythe Formula-I aldehyde but also the Formula-VI lactone aldehyde and theFormula-IV acetal 'ketone.

There is still further provided the new compounds 5 produced by theabove processes, all of which are use- LII ful intermediates in theseprocesses directed toward prostaglandins, viz. bicyclic aldehyde I inits optically active forms; acetal II; mono or dihaloketone III; ke- 1wherein E andM are both hydrogen, or wherein one of wherein Z is cisl-pent-2-enyl or 1-pent-2-ynyl; tetrahy- E and M is hydrogen and theother is formyl, and dropyranyl lactone XVIII of the formula wherein Wis l-pentyl, cis l-pent-2-enyl, or l-pent-2- o ynyl; the lactonebis(alkanesulfonate) IX of the for- H 5 mula 0 )OK i I" 9 g z I 10wherein Tl-IP is tetrahydropyranyl and Z is as defined -g above;tetrahydropyranyl lactol XIX of the formula moiso 0S02Ro on wherein R isalkyl of one to 5 carbon atoms, inclusive,

and W is as defined above; epoxide XXXVIII of the formula 5 0 A I s i io'ruP o'rnp wherein TI-IP and Z are as defined above; a Formula- 0 XXcompound of the formula 05in H wherein W is as defined above, andwherein o 3 H1 o'rln- O'Illl indicates attachment of the epoxide oxygento the side herein THP and Z are as defined above; and an oxachain in aor ,8 configuration; zohdme of bicyclic aldehyde I, ketone IV, orlactone dif t XL f the f l aldehyde VI with an optically activeephedrine. In these 0 compounds indicates attachment to the cyclopropanering in exo or endo configuration and to the side-chain 0 in a (S) or B(R) configuration. There are also pro- 5 40 vided the enantiomorphs andthe racemic mixtures of the above compounds.

\ 7 DESCRIPTION OF THE PREFERRED EMBODIMENTS 60110 The invention isfurther illustrated by, but not limited to, the following examples.wherein W is as defined above;

All temperatures are in degrees centigrade.

lactone diol XI represented y the mirror image of the Infraredabsorption spectra are recorded on a Perkinformula 0 Elmer model 421infrared spectrophotometer. Except A when specified otherwise, undiluted(neat) samples are 0 used. E The NMR spectra are recorded on a VarianA-6O spectrophotometer in deuterochloroform solutions withtetramethylsilane as an internal standard (downnsHm /W Circulardichroism curves are recorded on a Cary 3 on recordingspectropolarimeter. The collection of chromatographic eluate fractionslactone diol XVII of the formula starts when the eluent front reachesthe bottom of the i 60 column.

Brine, herein, refers to an aqueous saturated sodium chloride solution.

Preparation 1 Endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde (Formula Iis endo).

To a rapidly stirred suspension of anhydrous sodium carbonate (318 g.)in a solution of bicyclo[2.2.l]hepta-2,5-diene (223.5 g.) indichloromethane (1950 ml.) is added 177 ml. of 25.6% peracetic acidcontaining 6 23 g. of sodium acetate. The addition time is about 45min., and the reaction temperature is 26 C. The mixture is stirred foran additional 2 hrs. The reaction mixture is filtered and the filtercake washed with dichloromethane. The filtrate and washings areconcentrated under vacuum. About 81 g. of the resulting liquid isstirred with 5 ml. of acetic acid in 200 ml. of dichloromethane for 5.5hrs., then concentrated and distilled. The fraction boiling at 6973 C./mm. represents the desired Formula-I aldehyde, 73 g. NMR peaks at 5.9and 9.3 (doublet) 8.

The various Formula-l-to-IX intermediates, hereinafter, exist in exo aswell as endo forms. A preferred route to the exo form of the Formula-Ibicyclic aldehyde is by the steps shown in Chart G, using methods knownin the art. See South African Patent 69/4809 issued July 3, 1970. InFormulas XXVII to XXXVII, the attachment to the cyclopropane ring by astraight line extended downward at an angle to the right indicates theexo configuration. Thus, diazoacetic acid is added to a double bond ofcyclopentadiene to give an exoendo mixture of the Formula-XXVIIIbicyclo[3.l.O]- hexene substituted at the 6-position with a carboxyl.Tiic exo-endo mixture is treated with a base to isomerize the endoisomer in the mixture to more of the exo isomer. Next the carboxyl groupat 6 is transformed to an alcohol group and thence to the exo aldehydeof the Formula XXX.

EXAMPLE 1 dl Endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde Acetal ofEthylene Glycol (Formula II: R and R taken together are CH CH and isendo).

. ether and water. The ether layer is extracted with water, dried overanhydrous magnesium sulfate, and concentrated to the Formula-II bicyclicacetal, a light tan oil (70 g.); NMR peaks at 1.1, 1.6-2.9, 3.5-4.2,4.42, and 5.36.0 8.

Following the procedures of Example 1 but using the exo Formula-I (XXX)compound,.there is obtained the corresponding CHART G xxvn (-0()IlXXVI]! 24 continued l cmon XXIX xxx ouo

exo Formula-ll acetal.

Following the procedures of Example 1 but using either the endo or exoform of the Formula-I aldehyde and substituting for the ethylene glycolone of the following glycols: 1,2-propanediol, 1,2-hexanediol, 1,3-butanediol, 2,3-pentane'diol, 2,4-hexanediol, octanediol, 3,S-nonanediol, 2,2-dimethyl-1 ,3- propanediol,3,3-dimethyl-2,4-heptanediol, 4-ethyl-4- methyl-3,5-heptanediol,phenyl-l,2-ethanediol and lphenyl-l,2-propanediol, there are obtainedthe corresponding Formula-II acetals.

Following the procedures of Example 1 but using either the endo or exoform of the Formula-I aldehyde and substituting for the ethylene glycolone of the following alcohols: methanol, ethanol, l-propanol, or 1-butanol, there are obtained the corresponding Formula-II acetals.

EXAMPLE 2 dl Tricyclic Dichloroketone (Formula III: R, and R takentogether are CH CH and is endo).

Refer to Chart A. A solution of the Formula-II bicyclic acetal ofExample 1, (56 g.) and triethylamine g.) in 300 ml. of isomeric hexanes(Skellysolve B) is heated at reflux, with stirring, and treated dropwisewith dichloroacetyl chloride g.) in Skellysolve B over a 3-hour period.The mixture is cooled and filtered to remove solids. The filtrate andcombined Skellysolve B washes of the filtered solid is washed withwater, 5% aqueous sodium bicarbonate, and brine, dried over anhydroussodium sulfate and concentrated to the title compound, a dark brown oil(91 g.). An additional quantity (13 g.) is recovered from the filtercake and aqueous washes. Alternatively, the triethylamine is added to asolution of the bicyclic acetal and the dichloroacetyl chloride, or thetriethylamine and the dichloroacetyl are added separately butsimultaneously to a solution of the bicyclic acetal in Skellysolve B.

Following the procedures of Example 2 but using the exo Formula-IIcompound, there is obtained the corresponding exo Formula-III tricyclicdichloroketone.

Following the procedures of Example 2, but using the Formula-IIcompounds disclosed following Example 1, there are obtained thecorresponding Formula-II compounds.

EXAMPLE 3 dl Tricyclic Ketone (Formula IV: R and R are methyl and isendo).

A solution of the Formula-III dichloroketone of Example 2 (l04 g.) indry methanol (1 l.) is treated with ammonium chloride (100 g.) and smallportions of zinc dust. The temperature is allowed to rise to 60 C. After200 g. of zinc have been added, the mixture is heated under reflux foran additional 80 min. The mixture is cooled, the solids filtered off,and the filtrate concentrated. The residue is treated withdichloromethane and aqueous sodium bicarbonate and the mixture isfiltered. The dichloromethane layer is washed with 5% aqueous sodiumbicarbonate and water, dried, and concentrated to the title compound, adark brown oil (56 g.); infra-red absorption at 1760 cm.

Following the procedures of Example 3 but using the exo Formula-IIIcompound, there is obtained the corresponding exo Formula-1V tricyclicketone.

Following the procedures of Example 3 but using the Forrnula-IIIcompounds disclosed following Example 2, there are obtained thecorresponding Formula-IV compounds.

EXAMPLE 4 dl Tricyclic Lactone Acetal (Formula'V: R and R added over 40min. The mixture is stirred at C. for

1 hr., then warmed to reflux for 40 min. The mixture is cooled andfiltered, and the filtrate is washed with 5% aqueous sodiumbicarbonate-sodium thiosulfate, and then water. The dichloromethanelayer is dried over anhydrous sodium sulfate, and concentrated to theFormula-V acetal(6l g.). A portion (58g) is chromatographed on 2 kg. ofsilica gel packed in ethyl acetate- Skellysolve B (50-50). Elution with50-50, 70-30 and 80-20 ethyl acetate-Skellysolve-B yields a fraction(24.9 g.) shown by NMR to be a mixture of dimethyl acetal (V) andaldehyde (VI). A portion (226 g.) of the mixture is dissolved in 100 ml.of (60-40) formic acid-water and allowed to stand 1 hr. at 25 C. Thesolution is then concentrated under vacuum and the residue taken up indichloromethane. The dichloromethane solution is washed with 5% aqueoussodium bicarbonate and water, dried over sodium sulfate, andconcentrated to a brown oil (17.5 g.) which crystallizes on seeding.Trituration of the crystals with benzene leaves crystals of theFormula-VI aldehyde (9.9 g.). An analytical sample is obtained byrecrystallization from tetrahydrofuran, m.p. 7274 C. (corn); infraredabsorption peaks at 2,740, 1755, 1710, 1695, 1195, 1165, 1020, 955, and910, cm; NMR peaks at 1.8-3.4, 5.0-5.4, and 9.92 8.

Following the procedures of Example 4 but using the exo Formula-IVlactone acetal compound, there is obtained the corresponding exoFormula-V lactone acetal.

Likewise, following the procedures of Example 4 using the exo Formula-Vcompound, there is obtained the corresponding exo Formula-VI lactonealdehyde.

Following the procedures of Example 4 but using the Formula-IV compoundsdisclosed following Example 3, there are obtained the correspondingFormulaav compounds, and, thence, the corresponding Formula- VI lactonealdehydes.

EXAMPLE 5 stirred under nitrogen and to it is added 10 ml. of 1.6 m.n-butyllithium in n-hexane. After 10 min. a benzene solution of theFormula-VI tricyclic aldehyde (1.66 g.) of Example 4 is added dropwiseover 15 min. and the reaction mixture is heated at 6570 C. for 2.5 hrs.The mixture is cooled, the solids are filtered off and washed withbenzene, and the combined filtrate and washes are extracted with dilutehydrochloric acid and water. The solution is dried over sodium sulfateand concentrated under vacuum to an oil (3.17 g.). The crude Formula-VIIproduct is chromatographed on 400 g. of silica gel packed with (30-70)ethyl acetatecyclohexane and eluted with the same mixture. Fractions of20 ml. volume are collected. Fractions 47-50 are found to contain 0.8 g.of the desired Forrnula-VII tricyclic lactone heptene; NMR peaks at0.6-3.0, 4.4- 5.1, and 5.4 8. To minimize side reactions, it ispreferred that the Wittig reagent prepared from the phosphonium bromideand n-butyllithium be filtered to remove lithium bromide, and that theresultant solution be added to the benzene solution of the Formula-VItricyclic aldehyde in equivalent proportions.

Following the procedures of Example 5 but using the exo Formula-VIcompound, there is obtained the corresponding exo Formula-VII lactoneheptene. A preferred source of the exo form of the Formula-VI tricycliclactone aldehyde is by the steps shown in Chart H. Therein R is alkyl ofone to 4 carbon atoms. Thus, diazoacetic acid ester is added to a doublebond of cyclopentadiene to give an exo-endo mixture of the Formula-XXXIbicyclo[3. 1.0]hexene substituted at 6 with an esterified carboxyl, e.g.a methyl ester wherein R is methyl. The exo-endo mixture is treated witha base to isomerize the endo isomer to more of the exo isomer. Next thehexene is reacted with Cl C=C=0 generated in situ from dichloroacetylchloride and a tertiary amine or from trichloroacetyl chloride and zincdust as in step b of Chart A, to the Formula-XXXII dichloroketone.Successively, the dichloroketone is reduced as in step c of Chart A; theresulting Formula-XXXIII tricyclic ketone is converted to a lactoneester as in step d of Chart A; the lactone is saponified, thenacidified, to yield the Formula-XXXV compound with a carboxyl group atthe 6-position; then the carboxyl group is transformed to an alcoholgroup and finally to the exo aldehyde of Formula XXXVI].

EXAMPLE 6 dl Tricyclic Glycols (Formula VIII: W is l-pentyl and isendo). Refer to Chart A. Procedure A. A solution of the Formula-VIItricyclic CHART II COORn XXXI XXVII -continued lactone heptene ofExample (0.8 g.) in ml. of benzene is treated with osmium tetroxide 1.0g.) in ml. of benzene. After standing 24 hrs., the mixture is treatedwith hydrogen sulfide for 30 min., then filtered to remove a blacksolid. The filtrate is evaporated to an oil (393 mg.). An additionalquantity of oil (441 mg.) is recovered by suspending the black solid inethyl acetate and again treating with hydrogen sulfide. The oil ischromatographed on 100 g. of silica gel packed and eluted with (4060)acetone-dichloromethane. Fractions of ml. volume are collected. Twoerythro glycols of Formula Vlll are recovered, one more polar(slower-moving on the column) than the other. The faster-moving glycol,0.3 g., is found in fractions 20-30; the slower-moving one, 0.28 g., infractions 3l40.

Procedure B. A mixture of7 ml. of N-methylmorpholine oxide-hydrogenperoxide complex (see Fieser et al., Reagents for Organic Syntheses, p.690, John Wiley and Sons, lnc., New York, N.Y. (l967)), 8 ml. of THF, 14ml. of tert-butanol, and osmium tetroxide (2 mg.) in 2 ml. oftert-butanol is cooled to about 15 C.

A solution of the Formula-Vll tricyclic lactone heptene of Example 5(3.95 g.) in 12 ml. of Tl-lF and 12 ml. tertbutanol is then added slowlyover a period of 2 hrs. at a temperature of 15-20 C. The mixture isstirred for an additional 2 hrs., and to it is added a slurry of filteraid (for example magnesium silicate, 0.8 g.) in 14 ml. of watercontaining sodium thiosulfate (0.4 g.), and the solids removed byfiltration. The filtrate is concentrated under reduced pressure to anoil. Water (200 ml.) is added and the oil-water mixture is extractedwith several portions of dichloromethane. The dichloromethane solutionis dried over magnesium sulfate and then concentrated under reducedpressure to a mixture containing the title products.

Following the procedures of Example 6A and 6B but using the exoFormula-VII compound, there are obtained the corresponding exoFormula-VIII tricyclic glycols.

EXAMPLE 7 dl Bicyclic lactone bismesylate (Formula lX: R is methyl, W isl-pentyl, and is endo), and bicyclic lactone diol (Formula X: W isl-pentyl and indicates the a configuration). Refer to Chart A. Theslower moving Formula-VIII erythro glycol from Example 6 (277 mg.) isdissolved in 5 ml. of pyridine, cooled to 0 C. under nitrogen, andtreated with methanesulfonyl sisting of the Formula-IX bis-mesylatecompound. ,1

The above product is dissolved in 10 ml. of acetone and 5 ml. of water,left standing for 3 hrs. at 25 C., and concentrated under reducedpressure to remove the acetone. The solution is diluted with water andextracted with dichloromethane. The dichloromethane solution I is washedwith 5% sodium bicarbonate solution and brine, dried, and concentratedunder vacuumto an oil (200 mg.), consisting of the Formula-X product.

The Formula-X compound is obtained as a mixture of isomers in the a andB configuration. They are separated by silica gel chromatography and areused separately, e.g. in preparing the Formula-XIIbis(tetrahydropyranyl) ether. The undesired Formula-X isomer is recycledto isomerize it to a mixture of the a and B forms. For theisomerization, the l5-hydroxyl is oxidized to a l5-keto with selectiveoxidant, e.g., 2,3- dichloro-S ,6-dicyanol ,4-benzoquinone, activatedmanganese dioxide, or nickel peroxide (see Fieser et al., Reagents forOrganic Syntheses, John Wiley and Sons, lnc., New York, N.Y., pp. 215,637, and 731). Thereafter, the l5-keto compound is reduced with zincborohydride, by methods known in the art, to a mixture of the a and Bisomers, which are then separated by silica gel chromatography.

Following the procedure of Example 7, the fastermoving glycol istransformed to the same Formula-X product as above.

Following the procedures of Example 7 but using the exo Formula-Vlllcompound, there is obtained the corresponding exo Formula-IXbismesylate. This exo bismesylate is transformed to theFormula-X lactonediol by the procedures of Example 7 used for the endo compound.

The Formula-X lactone diol wherein Wis l-pentyl is transformed to dl-PGEand dl-PGF a and their alkyl esters using methods generally known in theart, e.g., following the steps of Chart C for dl-PGE and Chart E fordl-PGF a Example 8 dl Endo-bicyclo[3. l .0]hex-2-ene-6-carboxaldehydeAcetal of 2,2-dimethyl-1,3-propanediol (Formula ll: R and R takentogether are -CH C(CH CH and is endo).

Refer to Chart A. A solution of Formula-lendobicyclo[3.l.0]hex-2-ene-6-carboxaldehyde (48.6 g.), 2,2-dime'thyl-l,3-propanediol (140.4 g.), and oxalic acid (0.45 g.) inbenzene (0.9 l.) is heated under reflux for 4 hrs. The azeotropicallydistilled water is removed in a water separator. The reaction mixture iscooled, washed with 5% sodium bicarbonate solution and water. Thebenzene solution is dried over sodium sulfate, concentrated to an oil(93 g.), and distilled at reduced pressure. The fraction boiling at88-95 C./O.5 mm. is the desired title compound, 57.2 g., m.p. 5355 C.;NMR peaks at 0.66, 1.2, 3.42, 3.93, and 5.6 6; infrared absorption at1595, ll 10, 1015, 1005, 990, 965, 915 and 745 cm.

Following the procedures of Example 8 but using the exo Formula-lcompound, there is obtained the corresponding exo Formula-ll acetal.

EXAMPLE 9 dl Tricyclic dichloroketone (Formula III: R and R takentogether are CH C(CH -CH and is endo).

Refer to Chart A. Following the procedures of Example 2, the Formula-llcompound of Example 8 is transformed to the title compound, m.p. 97l00C., NMR peaks at 0.75, 1.24, 2.43 (multiplet), 3.42, 3.68, and 3.96(doublet) 8; infrared absorption at 3040, 1810, 1115. 1020, 1000, 980,845, and 740 cm.

EXAMPLE 10 d1 Tricyclic Ketone (Formula IV: R and R taken together areCH C(CH CH and is endo).

Refer to Chart A. Following the procedure of Example 3, the Formula-IIIdichloroketone of Example 9 is transformed to the title compound, anoil; NMR peaks at 0.75, 1.25, 3.0 (multiplet) and 4.0 (doublet) 8;infrared absorption at 1770 cm.

Following the procedures of Examples 3 and 10 but using thecorresponding exo Formula-III compound, there is obtained thecorresponding exo Formula-IV tricyclic ketone.

EXAMPLE 10A dl Tricyclic Lactone Acetal (Formula V: R and R takentogether are CH C(CH CH and is endo) and Tricyclic Lactone Aldehyde(Formula VI: is endo).

Refer to Chart A. Tricyclic ketone IV (Example 10, 12 g.) together withpotassium bicarbonate (6.1 g.) in 100 ml. of dichloromethane is cooledto about 10 C. Metachloroperbenzoic acid (12.3 g. of 85%) is addedportionwise at such a rate that the reaction temperature is kept below'30 C. Thereafter the mixture is stirred for 1 hr. and to it is added 150ml. of aqueous sodium bicarbonate solution containing 9 g. of sodiumthiosulfate. The dichloromethane layer is dried over sodium sulfate andconcentrated under reduced pressure. The oily residue contains theFormula-V lactone acetal: NMR peaks at 0.75, 1.23, 3.5 (quartet), 3.9(doublet) and 4.8 (quartet) 5; infrared absorption at 1760 cm.

Lactone acetal V (about 4.4 g.) in 60 ml. of 88% formic acid is leftstanding at 50 C. for one hour. The solution is then cooled, dilutedwith 60 ml. of 1 N. sodium hydroxide saturated with sodium chloride, andextracted with dichloromethane. The combined extracts are washed withsodium carbonate, dried over sodium sulfate, and concentrated underreduced pressure. The product crystallizes on standing, yielding theFormula-VI lactone aldehyde: m.p. 6973 C., NMR peaks at 5.2 (multiplet)and 10.0 (doublet) 3, and infrared absorption at 1755 cm.

Following the procedures of Example 10A, the corresponding exoFormula-IV tricyclic ketone yields the corresponding Formula-V and -VIcompounds.

EXAMPLE 1 l dl-PGE dl-l5-epi-PGE and their Alkyl Esters (Formula XXII ofChart D: indicates the 15a or 1513 configuration).

Refer to Charts A and D. Following the procedures of Examples l-4,inclusive, the endo Formula-I bicyclohexene aldehyde is transformed tothe endo Formula VI tricyclic lactone aldehyde.

Following the procedure of Example 5, but substituting for then-hexyltriphenylphosphine bromide the unsaturated phosphonium compoundderived from 1- bromo-3-hexyne, viz. l-hex-3-ynyltriphenylphosphinebromide, there is obtained the Formula-VII heptenyne compound wherein Yis l-pent-2-ynyl and is endo.

Successively, following the procedures of Examples 6 and 7, there areformed the Formula-VIII, -IX, and -X compounds wherein W isl-pent-2-ynyl and is endo for the moiety on the cyclopropane ring, andrepresents either the a or B configuration for the hydroxyl group on thesidechain. The Formula-X octenyne diol is obtained as a mixture ofisomers in the a and ,8 configuration. They are separated by silica gelchromatography and are used in preparing the Formula-XVII compounds. Theundesired Formula-X isomer is recycled and isomerized using theprocedures of Example 7. The a-configuration Formula-X octenyne diolwherein W is l-pent-2-ynyl is reduced to the Formula-XVII octadiene diolwherein Z is l-pent-2-enyl by reducing the C:: C moiety to cis CH=CH byhydrogenation over Lindlar catalyst as follows. To a solution of theFormula-X compound (20 mg.) in methanol (2 m1.) is added 5 mg. of 5%palladium-on-barium sulfate and 2 drops of synthetic quinoline. Themixture is stirred at about 25 C. and atmospheric pressure. The reactionis terminated when one equivalent of hydrogen is absorbed. The mixtureis filtered and the filtrate concentrated under vacuum. Ethyl acetate isadded and the solution is chromatographed on silica gel impregnated withsilver nitrate. The column is developed with isomeric hexanes(Skellysolve B) containing increasing amounts of ethyl acetate. Thosefractions containing the desired octadiene diol are combined andconcentrated to yield the Formula-XVII intermediate.

Following the steps of Chart D, the Formula-XVII compound, wherein Z isl-pent-2-enyl and represents the a configuration, is transformed to PGEusing methods generally known in the art. Thus, the Formula-XVII diol isconverted to the Formula-XVIII bis(- tetrahydropyranyl) ether; the 0x0group of the lactone is reduced to form the Formula-XIX lactol; theFormula-XX compound is formed by a Wittig reaction using w-chloro orw-bromopentanoic acid; the Formula-XX 9-hydroxy group is oxidized to the9-keto group of the Formula-XXI intermediate; and, finally, theprotective tetrahydropyranyl groups are removed by hydrolysis to yieldthe desired Formula-XXII dl- PGE Following the procedures of Example 1l, but substituting the exo Formula-I aldehyde for the endo aldehyde,there are obtained the Formula-VI, -VII, -VIII and -IX exo compoundswhich are converted to the Formula-X lactone diol, and thence to dl-PGEFollowing the procedures of Example 1 l for dl-PGE but substituting the156 (R)-configuration Formula-X octenyne diol for the S-configurationcompound, there are formed any of the Formula-XVIl-to-XXI interme diateswherein indicates the B configuration, and thence dl-15B-PGE ofFormula-XXII wherein indicates the B configuration.

Although Example 11 illustrates the embodiment of the process forpreparing PGE wherein the C-" C moiety of the Formula-X octenyne diol isreduced to cis CH=Cl-l immediately before forming thecis(tetrahydropyranyl) ether, it is within the scope of this inventionas shown in Charts A and D to carry out that reduction of C C to cisCH=)\ CH at any stage between the Formula-VIII glycol and the finaldl-PGE or dll 5/3-PGE Thus, the Formula-VIII compound wherein W islpent-2-ynyl and indicates attachment of the moiety to the cyclopropanering in exo or endo configuration, is subjected successively to thefollowing reactions:

a. replacement of the glycol hydrogens by an alkanesulfonyl group, R OS, wherein R is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of to 60 C. to form abicyclic lactone diol;

c. separation of the diols of a (S) and B (R) configuration;

d. transformation to a bis(tetrahydropyranyl) ether;

e. reduction of the lactone oxo group to a hydroxy group;

f. Wittig alkylation with a compound of the formula Hal(CH COOI-Iwherein Hal is bromo or chloro;

g. oxidation of the 9-hydroxy to oxo; and

h. transformation of the two tetrahydropyranyloxy group to hydroxygroups; with the proviso that, before or after any of the steps a to h,the C I C moiety is reduced to cis CI-I=CH, thereby forming dl-PGE ordl-l5,B-PGE By these procedures, there are formed the intermediates ofFormulas VIII, IX, and X, wherein W is either cis lpent-2-enyl orl-pent-2-ynyl; and the intermediates of Formulas XVIII, XIX, XX, andXXI, wherein Z is either cis l-pent-2-enyl or l-pent-Z-ynyl.

EXAMPLE l2 dl-PGF a and dl-l-epi-PGF a Esters (Formula XXVI of Chart E:indicates the a (S) or 153 (R) configuration).

Refer to Chart E. Following the procedures of Example l 1, there isprepared the a-configuration Formula- XVII octadiene diol. This diol istransformed to PGF a by the steps down in Chart E wherein indicates thea configuration, using methods known in the art. Thus, the Formula-XVIIdiol is converted to the Formula-XXV lactol by reducing the 0x0 group ofthe lactone; and the Formula-XXV compound is converted to dl-PGF a(Formula XXVI wherein indicates the S configuration) by a Wittigreaction using w-chloro or w-bromo-pentanoic acid.

Following the procedures of Example 12, but sutstituting the,B-configuration Formula-XVII octadiene diol for the a-configurationFormula-XVII octadiene diol, there is obtained dl-l 5,8-PGF (FormulaXXVI wherein indicates the ,8 configuration).

Although Example 12 illustrates one embodiment of the process forpreparing PGF a wherein the C- C moiety of the Formula-X octenyne diolis reduced to cis CH=CI-I- immediately before reducing the lactone oxogroup to a hydroxy group, it is within the scope of this invention asshown in Charts A and F to carry out the reduction of C C- to cis CH=CII at any stage between the Formula-VIII glycol and the final dl-PGF aand dl-lSB-PGF Thus, the Formula-VIII compound wherein W isl-pent-2-ynyl and indicates attachment of the moiety to the cyclopropanering in exo or endo configuration is subjected successively to thefollowing reactions:

a. replacement of the glycol hydrogens by an alkanesulfonyl group, R OS, wherein R is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of 0 to 60 C. to forma bicyclic lactone diol;

0. separation of the diols of a and ,8 configuration;

(1. reduction of the lactone oxo group to a hydroxy group; and

e. Wittig alkylation with a compound of the formula I-Ial(CH COOI-Iwherein Hal is bromo or chloro; with the proviso that, before or afterany of the steps a to e, the C C- moiety is reduced to cis CH=CH therebyforming dl-PGF or dl-lS -PGF By these procedures, there is formed theFormula-XXV intermediate wherein Z is either cis l-pent-2 enyl orl-pent-2-ynyl.

EXAMPLE 13 Resolution of Endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde(Formula I: is endo).

A. Formula-I endo-bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde (12.3 g.) andl-ephedrine (16.5 g.) are dissolved in about 150 ml. of benzene. Thebenzene is removed under vacuum and the residue taken up in about 150ml. of isopropyl ether. The solution is fil tered, then cooled to l3 C.to yield crystals of 2- endo-bicyclo[3. l.O]hex-2-en-6-yl)-3,4-dimethyl-5- phenyl-oxazolidine, l 1.1 g., m.p. 92C. Three recrystallizations from isopropyl ether, cooling each time toabout 2 C., yield crystals of the oxazolidine, 2.2 g., m.p. lOO-lO2 C.,now substantially a single isomeric form as shown by NMR.

The above re-crystallized oxazolidine (1.0 g.) is dissolved in a few ml.of dichloromethane, charged to a 20 g. silica gel column and eluted withdichloromethane. The silica gel is chromatography-grade, (Merck),0.05O.2 mm. particle size, with about 4-5 g. water per g. Fractions ofthe eluate are collected, and those shown by thin layer chromatography(TLC) to contain the desired compound are combined and evaporated to anoil (360 mg.). This oil is shown by NMR to be desired Formula-Icompound, endobicyclo[3.1.0]hex- 2-ene-6-carboxaldehyde, substantiallyfree of the ephedrine, in substantially a single optically activeisomeric form; called the isomer of Example l3-A herein. Points on thecircular dichroism curve are (A in nm, 9): 350, 0; 322.5, 4,854; 312,5,683; 302.5, 4,854; 269, O; 250, 2,368; 240, 0; and 210, 34,600.

B. The mother liquors of the oxazolidine are combined and evaporated tocrystals, taken up in dichloromethane, and chromatographed on silica gelas above to yield the enantiomorph of the above Formula-I compound,having the opposite optical rotation.

C. A preferred method of obtaining the isomeric oxazolidine which yieldsthe aldehyde of optical rotation opposite to that of the isomer ofExample l3-A is as follows. Following the procedure of A, above, theracemic .aldehyde is reacted with d-ephedrine to produce the oxazolidinein its diastereomeric forms. Recrystallization then yields the desiredoxazolidine, which is converted by hydrolysis to the desired opticallyactive aldeh de.

Following the procedures of Example 13, the exo Formula-I bicyclo[3.1.0]hex-2-ene-6-carboxaldehyde is converted to the oxazolidine of dorl-ephedrine and resolved into its optically active isomers.

EXAMPLE 14 Resolution of Acetal Ketone (Formula IV: R and R takentogether are CH C(CH CI-I and is endo).

A. A solution of 2.35 g. of the Formula-IV acetal ketone of Example 10(wherein the acetal is prepared from 2,2-dimethyl-1,3-propanediol) andl-ephedrine (1.65 g.) in benzene (15 ml.), together with 1 drop ofacetic acid, is heated at reflux for about 5.5 hrs., using a Dean andStark trap to remove water. The benzene is then removed by evaporationleaving the formed oxazolidine as solidswhich are dissolved in methanol.On

cooling the methanol solution, there is obtained one of thediastereomeric oxazolidines, 1.57 g, m.p. l6l166 C., [01],, 7.5 inchloroform, now substantially a single isomeric form as shown by NMR.NMR peaks at 0.63 (doublet), 0.72, 1.23, 2.38, 3.52, 3.95 (doublet) and4.94 (doublet) 8.

Following the procedure of Example 13, the above crystallizedoxazolidine is converted on a silica gel column to an optically activeisomer of the desired Formula-IV compound, 0.56 g., m.p. 43-47 C. [041+83 in chloroform; called the isomer of Example l4-A herein.

B. The mother liquor from A is concentrated and chilled to 1 3 C., toyield another diastereomeric oxazolidine, 1.25 g., m.p. l18l30 C.,[(111) +1l.7 in chloroform; NMR peaks at 0.63 (doublet), 0.72, 1.23,2.38, 3.52, 3.99 (doublet) and 5.00 (doublet) 8.

Following the procedure of Example 13, the crystallized oxazolidine isconverted on a silica. gel column to an optically active isomer of theFormula-IV compound.

C. Reaction of the above Example l4-B isomer with dephedrine by theprocedure of Example l4-A yields the enantiomorph of the oxazolidine ofExample 14A, m.p. 165 C., [a] +7.5 in chloroform.

Following the procedure of Example 13, the crystallized oxazolidine isconverted on a silica gelcolumn to an optically active isomer of thedesired Formula-IV identical to that obtained in Example l4-B above.

Following the procedures of Example 14, the exo Formula-IV acetal ketoneof Example is converted to the oxazolidine of dor l-ephedrine andresolved into its optically active isomers. I

Any one of the above resolved oxazolidines is hydrolyzed to the oxocompound and ephedrine by contact with water, preferably with an acidcatalyst, as is known in the art (see Elderfeld, I-leterocyclicCompounds, Vol. 5, page 394, Wiley, N.Y.', 1957). Thus, the oxazolidineof l-ephedrine and the Formula-IV acetal ketone (Example 14A, 5.0 g.) isstirred in a solution of tetrahydrofuran-water-acetic acid (25 ml.: 25ml.: 5 ml.) for 4 hrs. at about 25 C. under nitrogen. The solvents areremoved under reduced pressure at 25-40C., and the residue is mixed with25 ml. of water. The mixture is extracted several times with benzene,and the combined benzene layers are washed with water, dried over sodiumsulfate, and finally concentrated under reduced pressure to theoptically active Formula-IV acetal ketone having the same properties asreported above following section A. An alternate method of hydrolyzingthe oxazolidine is on a silica gel-water column according to Example 13,thereafter eluting the release oxo compound and recovering same byconventional means.

Example 15 Resolution of Tricyclic Lactone Aldehyde (Formula VI: isendo).

A. A solution of the endo Formula-VI lactone aldehyde (0.5 g.)'ofExample 4 and l-ephedrine (0.5 g.) in benzene ml.) is concentrated undervacuum to a residue. The residue is treated with diethyl etherto yieldcrystals of an oxazolidine mixture. Recrystallization of the mixturefrom methanol yields an oxazolidine, m.p. l33.4-l 34.5. Thereafter,hydrolysis of the oxazolidine on a silica gel column following theprocedure of Example 13 yields an optically active isomer correspondingto the mirror image of the Formula-VI lactone aldehyde, which isthereafter recovered by conventional" means and is hereinafteridentified as the isomer of Example l5-A.

B. Following the procedure of Example l5-A, but replacing l-ephedrinewith d-ephedrine in preparing the oxazolidine, the optically activeisomer corresponding to the Formula-VI lactone aldehyde is obtained,hereinafter identified as the isomer of Example l5-B.

Following the procedures of Example 15, the exo Formula-VI lactonealdehyde is resolved into its optically active isomers.

Example 16 Optically Active Tricyclic Glycol (Formula VIII of Chart A: Wis l-pentyl and is endo); PGE PGF their ent-Compounds and theirlS-Epimers.

Refer to Chart C. Following the procedures of Examples l to 6,inclusive, but using the Formula-I endobicyclo[3.l.0]hex-2ene-6-carboxaldehyde isomer of Example l-3-A, there isobtained the Formula-VIII tricyclic glycol, wherein W is l-pentyl and isendo, as an optically active isomer. Following the procedures of Example7, this isomer is transformed to the optically active Formula-IX andFormula-X compounds wherein Wis l-pentyl.

Likewise, using the Formula-I isomer of Example 13-C, there are obtainedthe enantiomorphic Formula- VIII, -IX, and -X compounds.

Each of the Formula-X isomers is transformed to the corresponding PGEent-PGE and their l5-epimers, using methods known in the art by the stepshown in Chart C. Thus, PGE is obtained from the optically activeFormula-X diol prepared from the Formula-l aldehyde isomer of Examplel3-A; ent-PGE is obtained from the enantiomorphic Formula-X diolprepared from the Formula-I aldehyde isomer of Example l3-C.

Furthermore, again using the optically active Formula-VIII, -IX, and -Xcompounds prepared above, but following the steps of Chart E, usingmethods generally known in the art, there are obtained the correspondingPGF a ent-PGF and their l5-epimers.

Following the procedures of Examples 1 to 6, inclusive, but substitutingthe optical isomers of the exo Formula-I aldehyde of Example 13 for theendo aldehyde, there are obtained the corresponding optically active exoFormula-VIII tricyclic glycols and Formula-IX bismesylates, which areconverted to the isomeric Formula-X diols and thence to thecorresponding PGE ent-PGE and their l5-epimers, PGF PGF and their l5epimers.

EXAMPLE l7 PGE ent-PGE and their IS-Epimers, (Formula XXII of Chart D:indicates the a or B configuration).

Refer to Chart D. Following the procedures of Example 13, the endoFormula-I bicyclohexene aldehyde is resolved into its two opticallyactive isomeric forms. Following theprocedures of Example 11 andthereafter, each of the Formula-I isomers is transformed to thecorresponding Formula-X diol in its a and ,8 configurations and thenceto the corresponding PGE ent-PGE and their; l5-epimers.

Following the procedures of Examples 14 and 15, the endo Formula-IVacetal ketone or the Formula-VI lactone aldehyde are resolved into theirrespective optically active isomeric forms. Following the procedures ofExample -1 l and thereafter, each of the Formula-IV or Formula-VIisomers is transformed to the corresponding Formula-X diol in its a andB configurations and thence to the corresponding PGE ent-PGE and theirIS-epimers.

Thus, PGE is obtained from the optically active Formula-X diol preparedfrom the Formula-[V Acetal ketone of Example l4-A or the Formula-VIlactone aldehyde of Example l5-B; ent PGE, is obtained from theenantiomorphic Formula-X diol prepared from the Formula-IV acetal ketoneof Example l4-C or the Formula-VI lactone aldehyde of Example l5-A.

Likewise, employing the exo forms of the Formula-l, -IV, and -VIcompounds, these are resolved into their respective optically activeisomeric forms and transformed to the corresponding Formula-X diol andthence to the corresponding PGE ent-PGE and their lS-epimers.

Likewise, following the procedures of Example 11 and thereafter, theoptically active Formula-VIII glycol in its isomeric forms, wherein W isl-pent-2-ynyl and indicates attachment of the moiety to the cyclopropanering in exo or endo configuration is subjected sucessively to thefollowing reactions:

a. replacement of the glycol hydrogens by an alkanesulfonyl group, R OS-, wherein R is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of to 60 C. to form abicyclic lactone diol;

c. separation of the diols of a and B configuration;

d. transformation to a bis(tetrahydropyranyl) ether;

e. reduction of the lactone oxo group to a hydroxy group;

f. Wittig alkylation with a compound of the formula Hal-(Clhh-COOHwherein Hal is bromo or chloro;

g. oxidation of the 9-hydroxy to oxo; and

h. transformation of the two tetrahydropyranyloxy groups to hydroxygroups; with the proviso that, before or after any of the steps a to h,the C E C moiety is reduced to cis CH=CH, thereby forming PGE ent-PGE ortheir l-epimers.

EXAMPLE l8 PGF ent-PGF and their IS-epimers, (Formula XXVI of Chart F:indicates the a or B configuration).

Refer to Chart F. Following the procedures of Example 13, the endoFonnula-l bicyclohexene aldehyde is resolved into its two opticallyactive isomeric forms. Following the procedures of Example 12 andthereafter, each of the Fonnula-l isomers is transformed to thecorresponding Formula-X diol in its a and B configurations and thence tothe corresponding PGF ent- PGE and their l5-epimers.

Following the procedures of Examples 14 and 15, the endo Formula-IVacetal ketone or the Formula-VI lactone aldehyde are resolved into theirrespective optically active isomeric forms. Following the procedures ofExample 12 and thereafter, each of the Formula-IV or Formula-VI isomersis transformed to the corresponding Formula-X diol in its a and Bconfiguration and thence to the corresponding PGF;, ent-PGF a and theirl5-epimers.

Likewise, employing the exo forms of the Formula-l, -IV, and -VIcompounds, these are resolved into their respective optically activeisomeric forms and transformed to the corresponding Formula-X diol inits a and B configuration and thence to the corresponding andthereafter, the optically active Formula-VIII glycol in its isomericforms, wherein W is l-pent-Z-ynyl and indicates attachment of the moietyto the cyclopropane ring in exo or endo configuration is subjectedsucces sively to the following reactions:

a. replacement of the glycol hydrogens by an alkanesulfonyl group, R OS-, wherein R is alkyl of one to 5 carbon atoms, inclusive;

b. mixing with water at a temperature in the range of 0 to 60 C. to forma bicyclic lactone diol of S and R configuration;

c. separation of the diols of S and R configuration;

d. reduction of the lactone oxo group to a hydroxy group; and

e. Wittig alkylation with a compound of the formula Hal (CH COOH whereinHal is bromo or chloro; with the proviso that, before or after any ofthe steps a to e, the C C- moiety is reduced to cis CH=CH, therebyforming PGF a ent- PGF a or their IS-epimers.

EXAMPLE 19 d] Tricyclic Lactone Epoxide (Formula XXXVIII: Y is n-pentyl,indicates attachment to the cyclopropane ring in exo or endoconfiguration, and

indicates attachment of the epoxide oxygen to the side chain in a or Bconfiguration).

Refer to Chart B. A mixture of the Formula-VII tricyclic lactone hepteneof Example 5 (2.02 g.) and potassium bicarbonate (0.8 g.) in 12 ml. ofdichloromethane is treated with peraceticacid (2 ml. of 40% in 8 m1. ofdichloromethane) added dropwise over 10 min. After the starting materialhas been converted to the product as shown by TLC (about 45 hrs. at 25C), the mixture is diluted with 30 ml. of dichloromethane and washedtwice with 5% sodium bicarbonate containing sodium thiosulfate (0.5 g.).The dichloromethane solution is dried over anhydrous sodium sulfate andconcentrated under reduced pressure to a residue of the title product,2.18 g., NMR peaks at 0.6-3.3, 4.8 (broad) 8.

EXAMPLE 20 dl Bicyclic Lactone Diformate (Formula XL: Y is npentyl andis alpha and beta). Refer to Chart B.

Procedure A. A solution of the mixed Formula-VIII glycols (Formula XXXIXwherein M and E are hydrogen) of Example 6 (2.38 g.) in 40 ml. of 100%formic acid is left standing 5.5 hrs. at about 25 C. The mixture is thenconcentrated under reduced pressure to an oily residue. The residue istreated with a solution of phosphate buffer (ph 6.8) and about 10%sodium bicarbonate and extracted with dichloromethane. Thedichloromethane solution is dried over sodium sulfate and concentratedunder reduced pressure to a residue containing the title product, 2.66g.

Procedure B. A solution of the Formula-XXXVI]! epoxide of Example 19(10.0 g.) in ml. of a mixture of acetone-water-formic acid (7023012 byvolume) is left standing 55 min. at least 25 C. The mixture isconcentrated under reduced pressure to a residue. The residue is treatedwith 5% sodium bicarbonate, saturated with sodium chloride, andextracted with ethyl acetate. The ethyl acetate solution is dried overmagnesium sulfate and concentrated under reduced pressure to a mixtureof glycol XXXIX (M and E are hydrogen) and diol X, 11.7 g.

A solution of the above glycol-diol mixture in 350 ml. of 100% formicacid is left standing 2 hrs. at about 25 C. The mixture is thenconcentrated under reduced pressure and the residue taken up indichloromethane. The dichloromethane solution is washed with 5% sodiumbicarbonate, dried over sodium sulfate and concentrated to a residuecontaining the title product, 13.2

Procedure C. A solution of the Formula-XXXVIII epoxide of Example 19(2.18 g.) in 40 ml. of 100% formic acid (see for example Winstein etal., J. Am. Chem. Soc. 74, l 120 (1952)) is stirred under nitrogen for2-3 hrs. at about C., monitoring the reaction by TLC. The mixture isconcentrated under reduced pressure to a residue. The residue is takenup in 50 ml. of dichloromethane and the solution washed with 5% sodiumbicarbonate. The dichloromethane solution is dried over sodium sulfateand concentrated under reduced pressure to a residue containing theFormula-XL title product, 2.92 g.

EXAMPLE 21 d1 Bicyclic Lactone Diol (Formula X: W is l-pentyl and isalpha or beta).

Refer to Chart B. A solution containing the Formula- XL diformates ofExample 20 (2.92 g.) in 10 ml. of methanol is stirred with potassiumbicarbonate (0.2 g.) for 0.5 hr. The mixture is then filtered and thefiltrate is diluted with 50 ml. of dichloromethane. The solution iswashed with brine, dried over magnesium sulfate, and concentrated underreduced pressure to a residue. The residue is chromatographed on silicagel (810 g.) packed in acetone-dichloromethane (:70), eluting withacetone-dichloromethane (3045% acetone) and collecting 200 ml.fractions. Fractions shown by TLC to contain the desired products freeof starting materials and impurities are combined, for example fractions20-25 contain the X B title compound and fractions 26-35 contain the X atitle compound. Concentration of the respective fractions yields thetitle compounds: diol X3 0.66 g.; diol X 0.76 g.

Example 22 d1 Tricyclic Lactone Monoformate (Figure XXXIX: M and E arehydrogen or formyl, Y is l-pentyl, and indicates attachment to thecyclopropane ring in endo configuration, and to the side chain in alphaor beta configuration).

A solution of the mixed Formula-VIII glycols (Formula XXXIX wherein Mand E are hydrogen) of Example 6 (2.38 g.) in ml. of 100% formic acid isleft standing 0.5 hr. at about 25 C. The mixture is then concentratedunder reduced pressure. The residue is treated with a solution ofphosphate buffer (pH 6.8) and about 10% sodium bicarbonate and extractedwith dichloromethane. The dichloromethane solution is dried over sodiumsulfate and concentrated under reduced pressure. The residue isseparated by chromatography on silica gel, combining those fractionsshown by TLC to contain the title compound. Concentration of thosefractions yields the title compound. R,=0.2 in ethyl acetate-SkellysolveB (40:60) on TLC plates.

Example 23 PGF a and 15B-PGF a Refer to Chart E.

A. Optically active tricyclic lactone acetal V. A mixture of theFormula-IV acetal ketone isomer of Example l4-A (12.0 g.) and potassiumbicarbonate (6.1 g.) in 100 ml. of dichloromethane is treated withmchloroperbenzoic acid (12.3 g. of in portions, with stirring andcooling to maintain the temperature below 30 C. After 2 hrs., 150 ml. of5% sodium bicarbonate solution containing 9 g. of sodium thiosulfate isadded. The dichloromethane layer is dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue is recrystallizedfrom ethyl acetate as the Formula-V tricyclic lactone acetal wherein Rand R taken together are CH C(CH and is endo; m.p. 127130 C., NMR peaksat 0.80, 1.29, 3.45, 3.72, 3.94 (doublet), and 4.89 (multiplet) 5;infrared absorption peaks at 1765, 1230, l 185, 1160, 1120, 1100, 1095,1015, 1000, 980, 955, and 925 cm; [0th, +9 (methanol).

B. Optically active tricyclic lactone aldehyde V1. The acetal ketone ofExample 23-A above (4.43 g.) is dissolved in 60 ml. of 88% formic acidand held at about 50 C. for 1 hr. The solution is cooled and dilutedwith 60 ml. of 1 N. sodium hydroxide saturated with sodium chloride, andthen extracted with several portions of dichloromethane. Thedichloromethane extracts are washed with 20 ml. of 10% sodium carbonate,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting oil is triturated with isopropyl ether andseeded to yield crystals of the corresponding Formula-VI tricycliclactone aldehyde, m.p. 62.5-64 C., NMR peaks at 2.48 (doublet), 2.82(doublet), 3.10 (multiplet), 5.12 (multiplet), and 9.84 (doublet);infrared absorption peaks at 1755, 1710, and 1695; [041 -30 (methanol).

C. Optically active tricyclic lactone heptene V11. Following theprocedure of Example 5, the lactone aldehyde of Example 23-B above istransformed to the corresponding Formula-Vll optically active lactoneheptene; NMR peaks at 0.63.0, 4.5-5.2, and 5.7 8; infrared absorptionpeak at 1700 cm.

D. Bicyclic lactone diol X. Following the procedures of Examples 19 to21, the tricyclic lactone heptene of Example 23-C above is transformedto the corresponding optically active Formula-X and -X lactone diols.

E. Title compounds.- Following the methods known in the art, the abovediols are transformed to the corresponding PGF and 15,8-PGF products.

Following the procedures of steps C, D, and E above, the opticallyactive isomers of the Formula-VI aldehyde of Example 15 are transformedto PGF -type products. Thus, PGF a and ISB-PGF are obtained from theisomer of Example l5-B; ent-PGF and ent-l SB-PGF are obtained from theisomer of Example 15-A.

I claim:

1. 2-( Endo-bicyclo [3. l .0]hex-2-en-6-yl)-3 ,4- dimethyl-S-phenyloxazolidine, being characterized by a melting point of l03 C.

1. 2-(ENDO-BICYCLO (3,1,0)HEX-2-EN-6-LY)-3,4-DIMETHYL-5PHENYLOXAZOLIDINE, BEING CHARACTERIZED BY A MELTING POINT OF 100*-103*C.